Insulin and cortisol have opposing effects on glucose metabolism in peripheral tissue and in brain. Insulin increases the rate of glucose utilization, whereas cortisol reduces insulin-mediated glucose disposal. Furthermore, defects in responsivity to insulin and cortisol increase with aging and many contribute to the pathophysiology of Alzheimer's disease (AD). In particular, previous work has established a link between insulin resistance and apolipoprotein E (apoE) genotype. Despite the close relationship between insulin and cortisol action and their putative role in AD, no study has examined the interactive effects of these systems on memory in normal adults or in patients with AD. The propose studies will use both clinical and molecular memory in normal adults or in patients with AD. The proposed studies will use both clinical and molecular biological methods to address the question of whether insulin-cortisol interactions differ for patients of varying apoE genotypes with AD and with Mild Cognitive Impairment (MCI). A clinical study will be conducted to test the hypotheses that raising cortisol levels during insulin infusion will attenuate the typical memory-enhancing effect of insulin, whereas suppressing endogenous cortisol during insulin infusion will increase the typical memory-enhancing effect of insulin for normal adults and for patients with AD or MCI. The proposed studies will also examine potential mechanisms through which cortisol affects insulin signaling by examining the effect of chronic glucocorticoid elevations on insulin degrading enzyme (IDE) expression and activity, and on insulin receptor distributions in non-human primate brain. Furthermore, preliminary work suggests that IDE expression is reduced in AD brain tissue, and that the nature of this abnormality may differ according to apoE genotype. In the final specific aim, we will expand this work to examine in detail regional IDE expression and activity in normal and AD brain from patients of differing apoE genotypes.